A pericentric chromosome 16 inversion, inv(16)(p13;q22), is present in almost 100% of patients with the M4Eo subtype of acute myeloid leukemia. A fusion gene between CBFB, the gene for a subunit of transcription factor CBF, and MYH11, which codes for smooth muscle myosin heavy chain, is generated by this chromosome 16 inversion. This CBFB-MYH11 fusion gene is believed to play a key role in leukemogenesis. Several projects are ongoing in the lab to investigate the mechanisms through which this fusion gene contributes to leukemia. (1) Using a mouse knock-in model we have previously shown that Cbfb- MYH11 dominant negatively suppresses the CBF function and blocks embryonic and adult hematopoiesis. Now using N-ethyl-N-nitrosourea (ENU) and retroviral mutagenesis we have shown that Cbfb-MYH11 expression is responsible for leukemogenesis by blocking myeloid and lymphoid differentiation, and that contribution from another oncogene is required for leukemia development. Identification of such cooperating oncogenes is underway. (2) Using cDNA microarray technology we are looking for genes whose expression is altered by CBFB-MYH11 in leukemic cells. Identification of such genes will help us understand the leukemia formation process and provide more therapeutic targets. (3) More mouse models are being generated through ES cell gene targeting techniques for further in-depth analysis of CBFB and/or CBFB- MYH11 functions in hematopoiesis and leukemogenesis. Some of the models will direct spatially and temporally controlled gene expression; while others are generated with detectable tags (e.g., green fluorescent protein) inserted to the pertinent genes. - bone marrow, genetics, hematology, leukemia